Written by |Consistent in the depositBrown adipose tissue（brown adipose tissue,batPrimarily through UCP1 for energy consumption, an increase in BAT in the body is associated with weight loss and a lower risk of cardiovascular disease。In addition to BAT, there is another type of thermogenic fat cell in the human body, namelyBeige fat cells(beige cells), which are mainly found in the subcutaneous white adipose tissue, are transformed by the process of browning or beige under cold stimulation or pharmacological action。The GPCR downstream GS signaling pathway plays an important role in brown and beige fats, and it is able to promote lipolysis as well as UCP1-mediated energy expenditure through CAMP-PKA signaling。In addition to PKA, CAMP can also directly activate some downstream proteins, such as EPAC. EPAC plays an important role in the leptin signaling pathway, insulin secretion, and phosphorylation of AKTHowever, it has not been studied whether it regulates energy expenditure and thermogenesis in brown or beige adipocytes. Recently, from the University of Bonn, Germanyalexander pfeiferThe team is innature cell biologyThe article was published in the journalepac1 enhances brown fat growth and beige adipogenesisThey demonstrated the effects of CAMP-EPAC1 in brown fat and beige adipocytes and found that EPAC1 signaling promoted BAT proliferation, browning of white adipocytes, and energy expenditure. 
The researchers first detected the expression levels of rapgef3, the gene encoding epac1, and rapgef4, the gene encoding epac2, in adipose tissue, and found that the expression level of rapgef3 in brown adipose tissue and beige adipose tissue was higher than that in white adipose tissue, indicating that its role was mainly in brown adipose tissue and beige adipose tissue. The researchers selected 007, an agonist of EPAC1, to detect the effect of EPAC1 after activation, and the results showed that the activation of EPAC1 promoted the accumulation of lipid droplets in BAT fat precursor cells, the up-regulation of the expression of thermogenic genes UCP1 and PparGC1A, and the increase of protein levels, as well as the increase in the expression level of mitochondrial oxphos complex. These results suggest that EPAC1 does promote brown adipogenesis through UCP1. withNorepinephrine（noradrenaline,naDirect activation of PKA has a different effect, and direct activation of EPAC1 does not quickly activate brown adipocytes. Further phosphoproteomic experiments showed that direct activation of EPAC1 promoted phosphorylation of mTorc1 substrate, which induced cell proliferation. Activation of PKA promotes phosphorylation of CDK1. In addition to this, both promote the phosphorylation of ERK12. The researchers found that MEK ERK inhibitors could inhibit the proliferation of brown adipocytes induced by 007 and Na treatment, and EPAC1 inhibitors could inhibit Na-induced ErK12 phosphorylation, the above results showed that Na-induced ERK12 phosphorylation was required by EPAC, and ERK12 phosphorylation was required for brown adipocyte proliferation, and Na-induced brown adipocyte proliferation was achieved by EPAC1. Later, the researchers activated EPAC1 in white adipocytes and found that it did not cause ERK1 2 phosphorylation and cell proliferation, which is completely different from the effect in brown adipocytes, where 007 treatment up-regulated genes such as UCP1, PGC1A, Cox8b and TFAM, reduced the size of lipid droplets, and promoted the differentiation of white adipose tissue into brown adipose tissue. The researchers conducted in vivo experiments and found that 007 treatment in mice for one week significantly increased the total amount of BAT and cell density in mice, as well as the expression of UCP1 and BAT-mediated energy expenditure. Knockout of RapgeF3 can reduce the total amount of BAT in mice under cold stimulation, impair the function of BAT, reduce oxygen consumption, and reduce the expression levels of UCP1 and thermogenesis marker genes. Finally, the researchers found that activation of EPAC1 was able to reduce the weight gain caused by high-fat feeding in mice. The above results were validated in human fat cells. In conclusion, this studyIt was found that CAMP-EPAC1 signaling can promote the proliferation of brown adipocytes, promote the browning of white adipocytes, promote thermogenesis and weight loss, and EPAC1 can be used as a new target for obesity**. It is worth mentioning that on the same day, the American Beth Israel Deaconess Medical Centerevan d. rosenPublished the News & Views articleepac1 boosts thermogenic adipocyte formation, commented on the article. 
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References
1. wolfrum, c. &gerhart-hines, z. fueling the fire of adipose thermogenesis.science375, 1229–1231 (2022).2. van marken lichtenbelt, w. d. et al. cold-activated brown adipose tissue in healthy men.n. engl. j. med.360, 1500–1508 (2009).3. kajimura, s., spiegelman, b. m. &seale, p. brown and beige fat: physiological roles beyond heat generation.cell metab.22, 546–559 (2015).4. cannon, b. &nedergaard, j. brown adipose tissue: function and physiological significance.physiol. rev.84, 277–359 (2004).5. yan, j. et al. enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic amp isoform 1.mol. cell. biol.33,918–926 (2013).6. kai, a. k. l. et al. exchange protein activated by camp 1 (epac1)-deficient mice develop β-cell dysfunction and metabolic syndrome.faseb j
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